Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects...

Sepsis survivors suffer from additional morbidities, including higher disk of readmissions, nervous system disturbances and cognitive dysfunction, and increased mortality, even several years after the initial episode of sepsis. In many ways, the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging. Since telomere shortening is a hallmark of aging, we investigated whether sepsis also leads to telomere shortening. Male balb/c mice were divided into two groups: the control group received 100 μl of normal saline intraperitoneally; the sepsis group received 15 mg/kg of bacterial lipopolysaccharide i...

Proximal metallic nanoparticles (NPs) could quench the electrochemiluminescence (ECL) emission of semiconductor quantum dots (QDs) due to Förster energy transfer (FRET), but at a certain distance, the coupling of light-emission with surface plasmon resonance (SPR) result in enhanced ECL. Thus, the modification strategies and distances control between QDs and metallic NPs are critical for the ECL intensity of QDs. In this strategy, a SPR enhanced ECL sensor based on DNA tetrahedral scaffolds modified platform was reported for the detection of telomerase activity...

Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters...

Dyskeratosis congenita (DC) is a very rare inherited disorder. It is caused by dysfunction of telomere maintenance. It involves RNA telomerase components relevant to various mutations leading to a classic triad of physical findings consisting of nail dystrophy of the hands and feet, mucosal leukoplakia, and reticular pigmentation of the skin, most commonly on the head, neck, and trunk. Bone marrow failure along with pulmonary complications and malignancies are all common causes of premature death in patients with DC as well as other abnormalities...

Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI...

T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT)...

The preparation of several new analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the nature of the side chain and the lactone ring. Their cytotoxic activity has been measured. In addition, their interaction with tubulin, their ability to inhibit the secretion of the vascular endothelial growth factor (VEGF) and the expression of angiogenesis and telomerase-related genes have been determined. Unexpectedly, and unlike pironetin, the lactones studied in this work do not interact with tubulin...

"Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion...

In tobacco, three sequence variants of the TERT gene have been described. We revealed unbalanced levels of TERT variant transcripts in vegetative tobacco tissues and enhanced TERT transcription and telomerase activity in reproductive tissues. Telomerase is a ribonucleoprotein complex responsible for the maintenance of telomeres, structures delimiting ends of linear eukaryotic chromosomes. In the Nicotiana tabacum (tobacco) allotetraploid plant, three sequence variants (paralogs) of the gene coding for the telomerase reverse transcriptase subunit (TERT) have been described, two of them derived from the maternal N...

A growing body of evidence suggests that microRNA-138 (miR-138) functions as a tumor suppressor, and is involved in tumor initiation, development and metastasis in certain types of human cancers. However, the function and underlying molecular mechanism of miR-138 in cervical cancer remains unclear. Therefore, the purpose of the present study was to investigate the clinical significance of miR-138 expression in cervical cancer, and to evaluate its role and underlying mechanisms in cervical cancer. The present study indicated that miR-138 expression was significantly downregulated in cervical cancer tissues and cell lines, and that the low miR-138 expression was negatively associated with advanced FIGO stage and lymph node metastasis (P<0...

Telomerase maintains telomere length at the ends of linear chromosomes using an integral telomerase RNA (TER) and telomerase reverse transcriptase (TERT). An essential part of TER is the template/pseudoknot domain (t/PK) which includes the template, for adding telomeric repeats, template boundary element (TBE), and pseudoknot, enclosed in a circle by stem 1. The Tetrahymena telomerase holoenzyme catalytic core (p65-TER-TERT) was recently modeled in our 9 Å resolution cryo-electron microscopy map by fitting protein and TER domains, including a solution NMR structure of the Tetrahymena pseudoknot...

To identify an effective ligand that binds to a G-quadruplex structure but not a double-stranded DNA (dsDNA), a set of biophysical and biochemical experiments were carried out using newly synthesized cyclic ferrocenylnaphthalene diimide (cFNDI, 1) or the non-cyclic derivative (2) with various structures of G-quadruplex DNAs and dsDNA. Compound 1 bound strongly to G-quadruplexes DNAs (10(6)M(-1) order) with diminished binding to dsDNA (10(4)M(-1) order) in 100mM AcOH-AcOK buffer (pH 5.5) containing 100mM KCl...

In mammals, postovulatory egg aging deteriorates egg quality possibly by mediating spontaneous exit from metaphase-II (M-II) arrest and/or inducing apoptosis. To test this possibility, present study was designed to investigate telomerase reverse transcriptase (TERT) expression, Bcl2 expression, and DNA fragmentation during postovulatory egg aging in vivo, as well as in vitro. Results suggest that postovulatory egg aging induced a time-dependent increase in the number of eggs undergoing spontaneous exit from M-II arrest in vivo, as well as in vitro...

In most eukaryotes, telomere maintenance relies on telomeric repeat synthesis by a reverse transcriptase named telomerase. To synthesize telomeric repeats, the catalytic subunit telomerase reverse transcriptase (TERT) uses the RNA subunit (TER) as a template. In the ciliate Tetrahymena thermophila,the telomerase holoenzyme consists of TER, TERT, and eight additional proteins including the telomeric-repeat single-stranded DNA binding protein Teb1 and its heterotrimer partners Teb2 and Teb3. Teb1 is paralogous to the large subunit of the general single-stranded DNA binding heterotrimer Replication Protein A (RPA)...

Mesenchymal stromal cells (MSC) are undifferentiated, multipotent adult cells with regenerative properties. They are particularly relevant for therapeutic approaches due to the simplicity of their isolation and cultivation. Since MSC show an expression pattern of cell surface marker, which is almost identical to fibroblasts, many attempts have been made to address the similarities and differences between MSC and fibroblasts. In this study we aimed to isolate murine MSC from bone marrow (BM) and kidney to characterize them in comparison to fibroblasts...